Ebolaviruses together with Marburgviruses form the family Filoviridae, a group of enveloped negative-strand RNA viruses responsible for severe hemorrhagic fevers in humans. Currently there are no effective vaccines or antiviral treatments available for human use. The Ebolavirus genome is about 19 kb long and encodes seven structural and several nonstructural proteins [1]. The single spike glycoprotein (GP) of Ebolaviruses is responsible for both cell targeting and virus entry [2] and thus is an important target of virus neutralizing antibodies [2]. Viral cell entry occurs through initial virus attachment to different cell-surface lectins recognizing highly N- and O-glycosylated GP [3, 4], followed by endocytosis via macropinocytosis [5] and proteolytic digestion of GP by cellular proteases cathepsin B and cathepsin L [6], leading to subsequent liberation of the receptor binding domain that interacts with an intracellular receptor, the Niemann Pick C1 protein (NPC1), an endo/lysosomal transporter of cholesterol [7]. It is generally accepted that conformational rearrangements associated with the interaction between NPC1 and the cleaved GP result in exposure of a fusion loop that facilitates membrane fusion and the liberation of the viral nucleocapsid into the cell cytoplasm [8]. Recently, several putative mechanisms were proposed to explain antibody-mediated neutralization of Ebolavirus [8, 9], including either inhibition of GP cleavage by cathepsins or the prevention of membrane fusion [9]. Although the protective efficacy of immune sera from survivors or of different cocktails of anti-GP antibodies varies in different publications [10-12], there is growing interest in the development of therapies against Ebola based on anti-GP antibodies, especially given the ongoing Ebola crisis in west Africa [13].
Previously we have presented data on a panel of 87 monoclonal antibodies (mAbs) directed against Ebola Zaire (EBOV) GP [14]. One such mAb, #3327, was found to display strong ebolavirus-neutralizing activity. In this current study we map the putative GP epitope recognized by this mAb, investigate the interaction between #3327 and GP and propose the mechanism involved in its neutralizing activity.